Site-Directed Perturbation of Protein Kinase C- Integrin Interaction Blocks Carcinoma Cell Chemotaxis

ABSTRACT Polarized cell movement is an essential requisite for cancer metastasis; thus, interference with the tumor cell motility machinery would significantly modify its metastatic behavior. Protein kinase Cα (PKCα) has been implicated in the promotion of a migratory cell phenotype. We report that the phorbol ester-induced cell polarization and directional motility in breast carcinoma cells is determined by a 12-amino-acid motif (amino acids 313 to 325) within the PKCα V3 hinge domain. This motif is also required for a direct association between PKCα and β1 integrin. Efficient binding of β1 integrin to PKCα requires the presence of both NPXY motifs (Cyto-2 and Cyto-3) in the integrin distal cytoplasmic domains. A cell-permeant inhibitor based on the PKC-binding sequence of β1 integrin was shown to block both PKCα-driven and epidermal growth factor (EGF)-induced chemotaxis. When introduced as a minigene by retroviral transduction into human breast carcinoma cells, this inhibitor caused a striking reduction in chemotaxis towards an EGF gradient. Taken together, these findings identify a direct link between PKCα and β1 integrin that is critical for directed tumor cell migration. Importantly, our findings outline a new concept as to how carcinoma cell chemotaxis is enhanced and provide a conceptual basis for interfering with tumor cell dissemination.

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Co-ordinate loss of protein kinase C and multidrug resistance gene expression in revertant MCF-7/Adr breast carcinoma cells

British Journal of Cancer ◽

10.1038/bjc.1997.225 ◽

1997 ◽

Vol 75 (9) ◽

pp. 1330-1335 ◽

Cited By ~ 26

Author(s):

J Budworth ◽

TW Gant ◽

A Gescher

Keyword(s):

Gene Expression ◽

Protein Kinase C ◽

Multidrug Resistance ◽

Protein Kinase ◽

Breast Carcinoma ◽

Carcinoma Cells ◽

Multidrug Resistance Gene ◽

Breast Carcinoma Cells ◽

Kinase C ◽

Mcf 7

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Protein Kinase Cα Determines HER2 Fate in Breast Carcinoma Cells with HER2 Protein Overexpression without Gene Amplification

Cancer Research ◽

10.1158/0008-5472.can-06-3936 ◽

2007 ◽

Vol 67 (11) ◽

pp. 5308-5317 ◽

Cited By ~ 23

Author(s):

Alessandra Magnifico ◽

Luisa Albano ◽

Stefano Campaner ◽

Manuela Campiglio ◽

Silvana Pilotti ◽

...

Keyword(s):

Protein Kinase ◽

Breast Carcinoma ◽

Gene Amplification ◽

Carcinoma Cells ◽

Protein Overexpression ◽

Her2 Protein ◽

Breast Carcinoma Cells ◽

Protein Kinase Cα

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Hyperexpression of integrin α5β1 promotes resistance of MCF-7 human breast carcinoma cells to doxorubicin via ERK protein kinase down-regulation

Biochemistry (Moscow) ◽

10.1134/s0006297917090048 ◽

2017 ◽

Vol 82 (9) ◽

pp. 1017-1024 ◽

Cited By ~ 1

Author(s):

G. E. Morozevich ◽

N. I. Kozlova ◽

O. Y. Susova ◽

A. Y. Lupatov ◽

A. E. Berman

Keyword(s):

Protein Kinase ◽

Breast Carcinoma ◽

Carcinoma Cells ◽

Human Breast Carcinoma ◽

Human Breast ◽

Down Regulation ◽

Integrin Α5β1 ◽

Breast Carcinoma Cells ◽

Human Breast Carcinoma Cells ◽

Mcf 7

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Collagen and Discoidin Domain Receptor 1 Partnership: A Multifaceted Role in the Regulation of Breast Carcinoma Cell Phenotype

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.808625 ◽

2021 ◽

Vol 9 ◽

Author(s):

Charles Saby ◽

Erik Maquoi ◽

Frédéric Saltel ◽

Hamid Morjani

Keyword(s):

Cell Proliferation ◽

Breast Carcinoma ◽

Type I Collagen ◽

Carcinoma Cell ◽

Carcinoma Cells ◽

Type I ◽

Collagen Remodeling ◽

Breast Carcinoma Cells ◽

Discoidin Domain Receptor ◽

Discoidin Domain Receptor 1

Type I collagen, the major components of breast interstitial stroma, is able to regulate breast carcinoma cell behavior. Discoidin domain receptor 1 (DDR1) is a type I collagen receptor playing a key role in this process. In fact, collagen/DDR1 axis is able to trigger the downregulation of cell proliferation and the activation of BIK-mediated apoptosis pathway. The aim of this review is to discuss the role of two important factors that regulate these processes. The first factor is the level of DDR1 expression. DDR1 is highly expressed in epithelial-like breast carcinoma cells, but poorly in basal-like ones. Moreover, DDR1 undergoes cleavage by MT1-MMP, which is highly expressed in basal-like breast carcinoma cells. The second factor is type I collagen remodeling since DDR1 activation depends on its fibrillar organization. Collagen remodeling is involved in the regulation of cell proliferation and apoptosis through age- and proteolysis-related modifications.

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CD24 expression and breast cancer stem cell phenotype

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.11106 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 11106-11106

Author(s):

G. Rappa ◽

F. Anzanello ◽

A. Lorico

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Breast Carcinoma ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Carcinoma Cells ◽

Cell Phenotype ◽

Cell Cycle Distribution ◽

Breast Carcinoma Cells ◽

The Relationship

11106 Background: Several studies suggest the existence of breast cancer-initiating cells (BCIC), responsible for tumor development and progression. Initial reports that only the CD44+CD24−/low subpopulation contains BCIC have been challenged by subsequent studies. We examined the relationship between CD24 and biological properties of breast cancer cells. Methods: MA-11 breast carcinoma cells, originating from bone marrow micrometastases, are CD44+ and have an heterogeneous expression of CD24 (214,000/cell; range 0–1,120,000). We have previously reported that upon in vitro culture as mammospheres under stem cell-like conditions, MA-11 cells acquired increased tumorigenicity and a CD44+CD24−/low phenotype. We have now investigated the relationship between CD24 expression and tumorigenicity in the MA-11 model. Results: Upon passage of MA-11 mammospheres in adherent culture, cells rapidly re-expressed CD 24. The rapid increase in CD24 was consistent with antigen up-regulation, not selection of CD24−/low cells. Exposure of adherent MA-11 cells to imatinib for 72h resulted in a reversible decrease in CD24 from 214,000 to 15,800/cell. CD44+CD24−/low cells, sorted by flow cytometry, generated CD44+CD24high, and CD44+CD24highgenerated CD44+CD24−/low. Immediately after sorting, >90% CD44+CD24−/low cells were in G0/G1. After 24–48 h in culture, cell cycle distribution, growth rate and invasiveness of the sorted cell populations were equivalent. Upon injection and s.c. growth, CD24 expression of CD44+CD24−/low populations and clones increased from 10,000 to 220,000/cell. Similarly, CD44+CD24−/low clones derived from human MCF-7 breast carcinoma cells formed tumors containing >99% CD44+CD24high cells. The average number of CD24 per cell was equivalent for tumors formed upon injection of CD44+CD24−/low, CD44+CD24+, mammosphere-derived cells or parental adherent MA-11 cells. The tumorigenic potentials of sorted CD44+CD24−/low, CD44+CD24−/lowsub-populations and clones in nu/nu mice were equivalent. Conclusions: CD44+CD24−/low breast cancer cells are not associated with increased tumorigenicity; the high CD24 level of mouse xenografts derived from both CD44+CD24−/low and CD44+CD24hi breast cancer cells suggests an important role for CD24 in tumor growth. No significant financial relationships to disclose.

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